Tony Berberabe, MPH

The latest findings from the ZUMA-5 clinical trial (NCT03105336) show a durable effect for treatment of patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL) with axicabtagene ciloleucel (axi-cel; Yescarta).

Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR (2022 Tandem Meetings)

, held in Salt Lake City, Utah, and virtually April 23-26, 2022, demonstrated a continued high response rate and activity in patients with relapsed/refractory FL and MZL. 

In patients with FL, investigators reported a median duration of response (DOR) of 38.6 months and that 57% of efficacy-eligible patients had an ongoing response at the data cutoff of March 31, 2021. In this population, median progression-free survival (PFS) was nearly 40 months, and median overall survival (OS) was not reached (NR). The overall response rate (ORR) was 94% (79% complete response [CR] rate).

In patients with MZL, after a median of 24 months, efficacy outcomes appeared to improve with longer follow-up, with median DOR and OS not yet reached. Median PFS was 17.3 months. Investigators reported that half of the patients with MZL had an ongoing response at data cutoff. The ORR was 83% in patients with MZL (63% CR rate).

According to the ZUMA-5 trial protocol, an updated efficacy analysis was conducted when 80 or more treated patients with FL had more than 24 months of follow-up. A total of 110 efficacy-eligible patients were analyzed: 86 patients with FL and 24 patients with MZL. Safety data were reported for all 149 patients treated with axi-cel (124 patients with FL and 24 patients with MZL).

“In the primary analysis of [ZUMA-5; n = 104], the ORR was 92% and investigators reported a 74% CR rate after a 17.5-month median follow-up,” study author Julio C. Chavez, MD, an associate member in the Lymphoma Section of the Department of Malignant Hematology at Moffitt Cancer Center, in Tampa, Florida, said. “Here, we report updated clinical and pharmacologic outcomes from ZUMA-5 with 2 or more years of follow-up.” Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of R/R large B-cell lymphoma and follicular lymphoma, both after more than 2 lines of systemic therapy.

Among patients with FL who progressed after less than 2 years after initial chemoimmunotherapy (POD24; n = 49), median DOR was 38.6 months. Median DOR was not reached in those without POD24 (n = 29). Median PFS was 39.6 months and NR in patients with and without POD24, respectively. Median time to next treatment (TTNT) was 39.6 months in all eligible patients with FL. Investigators reported that median OS was NR.

“Across key subgroups, long-term PFS rates in patients with FL were generally consistent,” Chavez said. Similarly, despite the limited sample size of the MZL population, the PFS rate at 12 months appeared to be consistent among key subgroups, including those patients treated with a prior Bruton tyrosine inhibitor.

Turning to safety, Chavez said the most common grade 3 or higher adverse events (AEs) were neutropenia (33%), decreased neutrophil count (28%), and anemia (25%). Seven percent of patients (6% in FL and 8% in MZL) experienced grade 3 or worse cytokine release syndrome (CRS) and 19% of patients (15% in FL and 36% in MZL) reported neurologic events. Chavez noted that most CRS cases (120 of 121) and neurologic events (82 of 87) of any grade resolved by data cutoff. Thirty-four percent of patients reported grade 3 or higher cytopenias 30 days or more post infusion (33% in FL and 36% in MZL), and the most common cytopenia reported was neutropenia in 29% of patients (27% in FL and 36% in MZL).

After data cutoff, grade 5 AEs occurred in 6 patients: 1 due to COVID-19 (unrelated), 1 COVID-19 pneumonia (related to axi-cel), 1 progressive multifocal leukoencephalopathy (related to axi-cel) and 2 cases of sepsis (both unrelated).

Chavez noted robust chimeric antigen receptor T-cell expansion in patients with FL and ongoing responses at 24 months than in patients who had relapsed. Pharmacokinetic findings were similar in patients with MZL.

Chavez said the long-term follow up in ZUMA-5 showed substantial and continued benefit of the CAR T-cell therapy. “Axi-cel maintained a manageable safety profile with no new safety signals,” he concluded.

Neelapu SS, Chavez JC, Sehgal AR, et al. Long-Term Follow-up Analysis of Zuma-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL). Presented at: the 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022. Abstract 75.

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In this population, median progression-free survival was nearly 40 months.

Durable Response Seen With Axi-Cel in Non-Hodgkin Lymphoma

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CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has shown benefit in patients with B-cell non-Hodgkin lymphoma. Early data indicate that this treatment is promising, with a high rate of durable remission, although longer follow up is necessary in order to confirm whether the responses translate to cures in patients with these indolent, difficult-to-treat diseases.

During the Society of Hematologic Oncology 2021 Annual Meeting on September 10, 2021, Caron A. Jacobson, MD, MMSC, medical director, Immune Effector Cell Therapy Program and senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts, discussed results from the ZUMA-5 trial (NCT03105336), provided a comparison between ZUMA-5 and the SCHOLAR-5 trials,

 and interim results from the ELARA study (NCT03568461).

ZUMA-5 evaluated axicabtagene ciloleucel (axi-cel; Yescarta) in 124 patients with follicular lymphoma (FL) and 22 patients with marginal zone lymphoma (MZL) who had undergone 3 lines of prior therapy. The primary end point was overall response rate (ORR), and key secondary end points were complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs).

“These were a group of patients at high-risk, with the majority [46.5%] having FLIPI scores greater than 3,” Jacobson, an assistant professor of medicine at Harvard Medical School, said. In addition, many patients (54.1%) were classified as POD24, ie, having progression of disease within 24 months of receiving their first anti-CD20 monoclonal antibody–containing therapy.

In ZUMA-5, ORR was 92% with a CR rate of 76%. For patients with FL, after 12 months of follow up, the ORR was 94% (n = 84) with a CR of 80%. For patients with MZL, the ORR was 85% (n = 20) with a CR rate of 60% (n = 12). “It is notable that 52% of patients who had had an initial partial response at first tumor restaging, went on to have a CR after a median of 2.2 months of follow-up,” Jacobson said in her presentation.

In patients with FL, median DFS, PFS, and OS have not been reached; among patients who had responded at a median follow-up of 18 months, 78% were maintaining their response. Jacobson said the MZL survival curves were quite immature because patients only needed one month of follow-up to be included in the efficacy analysis. “We are awaiting longer-term follow-up for this cohort,” Jacobson noted.

When outcomes by POD24 were reviewed, patients with FL and MZL with POD24 had a lower CR rate and a shorter DOR and PFS than those without POD24. “This was most notable in the MZL cohort, where only 58% of patients had a CR in the POD24 group compared with 75% and the median DOR was 11.1 months. Median PFS was 9.2 months for patients with POD24 compared with not reached for both end points for patients with MZL without POD24,” Jacobson explained.

The safety profile appeared more favorable than that observed with axi-cel in patients with diffuse large B-cell lymphoma (DLBCL) with only 7% of patients having grade 3 or greater cytokine release syndrome (CRS) and 19% of patients with grade 3 or greater neurologic events. Also, the median time to onset of CRS was later in FL and MZL at 4 days, compared with DLBCL at 2 days, according to findings from the ZUMA-1 study (NCT02348216).

Results from the SCHOLAR-5 study were presented at the 2021 European Hematology Association Meeting (EHA2021).

 This was a retrospective meta-analysis comparing clinical outcomes from the updated 18-month ZUMA-5 study to a matched sample from the SCHOLAR-5 study. Data from the pivotal DELTA trial (NCT01282424) evaluating idelalisib (Zydelig) was included in the SCHOLAR-5 cohort. Eighty-five patients in the SCHOLAR-5 study and 86 patients in ZUMA-5 were evaluable after propensity score weighing was applied to the cohorts.

In third-line or higher, the ORR was 49.9% in SCHOLAR-5 compared with 94.2% for an OR of 16.2 (95% CI, 5.6-46.9). The median PFS and OS were not reached in ZUMA-5 and in SCHOLAR-5 were 12.7 months and 59.8 months, respectively. “The analysis revealed a statistically significant improvement in both overall response rate from 49.9% to 94.2%, and a complete response rate from 29.9% to 79.2%,” Jacobson said. “This translates to an improvement in PFS, time-to-next treatment, and a statistically significant improvement in overall survival that was seen even within the first 3 years of follow-up.”

Another study that evaluates CD19-directed CAR T cell therapy in follicular therapy is the ELARA study.

 The study evaluated tisagenlecleucel (Kymriah) in relapsed FL in patients who are in the third line setting and beyond. Investigators reported a complete response rate of 66%, with an ORR of 86% and a median follow-up of 11 months. Jacobson noted that a high proportion of patients maintained their response and that the PFS and OS curves were like those presented in ZUMA-5.

Regarding safety, Jacobson said the toxicity profile for tisagenlecleucel in FL was improved over the toxicity for the agent in patients with DLBCL and was better than the safety profile of axicabtagene ciloleucel. Investigators reported that 48.5% of patients had any grade CRS and no patients had grade 3 or higher CRS. In terms of immune cell–associated neurologic syndrome (ICANS), 9.3% of patients had any grade ICANS and 1% of patients had grade 3 or higher ICANS.

According to Jacobson, other ongoing studies include ZUMA-5, explores axi-cel in patients with marginal zone lymphoma, the ongoing ELARA study, and the TRANSCEND study (NCT02631044), which evaluates lisocabtagene maraleucel (Breyanzi) in follicular lymphoma. Further, phase 1/2 studies that explore new agents include both allogeneic and natural killer CAR T-cells, as well as dual antigen targeting CARs that involve patients with indolent lymphomas.

“We are hopeful that these emerging therapies will change the course of these cancers and provide curative therapy for our patients,” concluded Jacobson.

1. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition, December 5-8, 2020. Abstract 700. Accessed September 8, 2021. 

https://ash.confex.com/ash/2020/webprogram/Paper136834.html


2. Ghione P, Patel A, Bobillo S, et al. A comparison of clinical outcomes from ZUMA-5 (axicabtagene ciloleucel) and the international scholar-5 external control cohort in relapsed/refractory follicular lymphoma (R/R FL). Presented at: European Hematology Association 2021 Virtual Congress. Abstract LB1904. Accessed September 8, 2021. 


3. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): Primary analysis of the phase 2 Elara trial. J Clin Oncol. 2021;39 (suppl 15): abstr 7508. doi: 10.1200/JCO.2021.39.15_suppl.7508

Positive data has been seen with CAR T-cell therapy in patients with indolent lymphoma.

CAR T-Cell Therapy's Continued Benefit in B-Cell Non-Hodgkin Lymphoma

have demonstrated efficacy across B-cell histologies. The therapies have also yielded durable remissions in patients with indolent B-cell non Hodgkin lymphoma. CAR T-cell therapy seems to be well-tolerated in this disease state.

Longer follow-up is needed to determine if these responses represent cures in these historically difficult-to-treat malignancies, according to Caron A. Jacobson MD, MMSC, medical director, Immune Effector Cell Therapy Program and senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts.

Jacobson discussed results from the ZUMA-5 trial (NCT03105336), provided a comparison between ZUMA-5 and the SCHOLAR-5 trials,

 and interim results from the ELARA study (NCT03568461) in a presentation at the Society of Hematologic Oncology 2021 Annual Meeting on September 10, 2021.

AlloCAR T Programs Halted Following Chromosomal Abnormality

In third-line or higher, the ORR was 49.9% in SCHOLAR-5 compared with 94.2% for an OR of 16.2 (95% CI, 5.6-46.9). The median PFS and OS were not reached in ZUMA-5 and in SCHOLAR-5 were 12.7 months and 59.8 months, respectively. “The analysis revealed a statistically significant improvement in both overall response rate from 49.9% to 94.2%, and a complete response rate from 29.9% to 79.2%,” Jacobson said (

). “This translates to an improvement in PFS, time-to-next treatment, and a statistically significant improvement in overall survival that was seen even within the first 3 years of follow-up.”

Another study that evaluates CD19-directed CAR T cell therapy in follicular therapy is the ELARA study.3 The study evaluated tisagenlecleucel (Kymriah) in relapsed FL in patients who are in the third line setting and beyond. Investigators reported a complete response rate of 66%, with an ORR of 86% and a median follow-up of 11 months. Jacobson noted that a high proportion of patients maintained their response and that the PFS and OS curves were like those presented in ZUMA-5.

1. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition, December 5-8, 2020. Abstract 700. Accessed September 8, 2021.


2. Ghione P, Patel A, Bobillo S, et al. A comparison of clinical outcomes from ZUMA-5 (axicabtagene ciloleucel) and the international scholar-5 external control cohort in relapsed/refractory follicular lymphoma (R/R FL). Presented at: European Hematology Association 2021 Virtual Congress. Abstract LB1904. Accessed September 8, 2021.


3. Schuster SJ, Dickinson MJ, Dreyling MH, et al. Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): Primary analysis of the phase 2 Elara trial.

. 2021;39 (suppl 15): abstr 7508. doi: 10.1200/JCO.2021.39.15_suppl.7508

Longer follow-up is needed to determine the potential of CAR T-cell therapies in difficult-to-treat malignancies.

Investigating CAR T-Cell Therapies in Indolent Lymphoma

bb21217, an enriched CAR T-cell therapy, improved responses and prolonged duration of response (DOR) compared with non-enriched CAR T cells in patients with relapsed/refractory multiple myeloma, according to results of a phase I escalation and expansion study (NCT03274219) that were presented during the 2020 ASH Annual Meeting.

Additionally, the percentage of senescent CAR T cells decreased in the presence of the enriched CAR molecule (CAR+), called bb21217, according to investigators.

The study enrolled 74 heavily pretreated patients with relapsed/refractory multiple myeloma who had undergone ≥ 3 prior lines of treatment. The dose-escalation phase of the study used a standard 3 + 3 pattern, with CAR+ T-cell doses at 150 × 106 (n = 12), 300 × 106 (n = 6), and 450 × 106 (n = 6). In the expansion phase of the study, patients received CAR+ T cell doses of 300 × 106 (n = 8) and 450 × 106 (n = 37).

The primary end point was safety and secondary end points were response, progression-free survival (PFS), minimum residual disease (MRD), and CAR+ T-cell expansion and persistence. In the presentation, lead investigator Melissa Alsina, MD, presented data on 69 patients who had a median follow up of 5.8 months.

Median age was 62 years (range, 33-76), the majority were men (61%), and the majority were ECOG performance status 1 (59%). Prior to enrollment, 26% were International Staging System stage I, 25% were stage 2, and 19% were stage III. Thirty-three percent of the patients were found to have high-risk cytogenetics including del(17p), t(4;14), or t(14;16).

The median number of prior regimens was 6, including 97% receiving lenalidomide (Revlimid), 94% receiving a CD38 antibody, 93% receiving pomalidomide (Pomalyst), and 91% receiving bortezomib (Velcade). Eighty percent of patients were double refractory and 64% were triple refractory.

“Regarding safety and tolerability, the most common adverse event [AE] was grade 3/4 cytopenias,” said Alsina, an associate professor of medicine in the Blood and Marrow Transplant Program and head of the Multiple Myeloma Transplant Program, both at Moffitt Cancer Center in Tampa, Florida. “These were not dose related,” she added.

Median time to recovery for grade 3/4 neutropenia and grade 3/4 thrombocytopenia was 2.0 months and 2.2 months, respectively. Grade 3/4 infection was reported in 26% of patients, with 1 death from infection reported within 6 months, but in the absence of disease progression.

There were 2 deaths reported within 8 weeks of the bb21217 infusion, both attributed to cytokine release syndrome (CRS).

Regarding CRS, the median time to onset was 2 days (range, 1-20) with 70% of patients reporting any grade CRS. The majority of patients reported 65% of grade 1/2 CRS, 1% reported grade 3 and 3% reported grade 5. To alleviate CRS symptoms, 31 patients received tocilizumab (Actemra) and 10 patients received the combination of tocilizumab and corticosteroid.

Time to onset for neurotoxicity was 7 days (range, 1-24) and median duration was 2 days (range, 1-188). “Cases of neurotoxicity were rare and observed in 16% of patients for any grade neurotoxicity,” Alsina said. Two grade 3 events were observed: 1 case of encephalopathy occurring with grade 5 CRS and 1 case of dizziness/vertigo that resolved within 48 hours. One grade 4 encephalopathy was reported. The patient was treated with tocilizumab, corticosteroid, and cyclophosphamide.

The objective response rate (ORR) was reported as 68% with a stringent complete response (sCR)/CR of 29% and a very good partial response (VGPR) of 25%. Median time to first response was 1 month.

“We tested for MRD by next-generation sequencing, and the majority of the patients that had PR, were also MRD negative,” Alsina said. “Further, all the patients who were in CR were MRD negative,” she said.

Alsina noted that midway through enrolling patients for the 450 × 106 dose level, there was an update in the manufacturing process of the CAR T cells. The update required enrolling an additional 29 patients in the expansion phase of the trial. “When these patients were evaluated, we noted an ORR of 84% and an sCR/CR rate of 32%. Prior to this change, the ORR was 68%,” she said. The incidence of AEs, including all grades and ≥ grade 3 CRS and neurotoxicity, were similar between the 2 manufacturing processes.

When looking at the DOR, even after only a median follow up of 7 months, the median DOR was 17 months for the whole cohort. When stratified by dose, the 150 × 106 dose had an 11.5-month DOR, whereas the median DOR for the 300 × 106 and 450 × 106 doses were not evaluable.

The investigators noted that the enrichment for memory-like T cells was associated with peak CAR T expansion and response. Specifically, patients exhibited a significantly better peak expansion because of a higher proportion of memory-like T cells observed. It is believed this higher proportion was associated with the use of the bb21217 product. This is beneficial because a higher proportion of memory-like T cells is associated with numerically less disease progression.

The phase I study has completed enrollment and follow-up is ongoing.

“ORR, CR, and MRD negative rates are promising across the study and at the recommended phase 2 dose,” Alsina said. “Long-term CAR T cell persistence was observed in 6 of 11 evaluable patients at month 12 and 3 of 6 evaluable patients at month 18,” she concluded.

Alsina M, Shah N, Raje NS, et al. Updated results from the phase I CRB-402 study of anti-BCMA CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 130.

The enriched chimeric antigen receptor T-cell therapy improved responses and prolonged duration of response in patients with relapsed/refractory multiple myeloma.

bb21217 Continues to Yield Improved, Durable Responses in Multiple Myeloma

The enriched chimeric antigen receptor (CAR) T-cell therapy bb21217 improved responses and also prolonged duration of response (DOR) compared with non-enriched CAR T cells in patients with relapsed/refractory multiple myeloma, according to results of a phase I escalation and expansion study (NCT03274219) that were presented during the 2020 ASH Annual Meeting. Additionally, the percentage of senescent CAR T cells decreased in the presence of the enriched CAR molecule (CAR+), called bb21217, according to investigators.

The study enrolled 74 heavily pretreated patients with relapsed/refractory multiple myeloma who had undergone ≥ 3 prior lines of treatment. The dose-escalation phase of the study used a standard 3 + 3 pattern, with CAR+ T-cell doses at 150 × 10

 (n = 6). In the expansion phase of the study, patients received CAR+ T cell doses of 300 × 10

Alsina noted that midway through enrolling patients for the 450 × 10

 dose level, there was an update in the manufacturing process of the CAR T cells. The update required enrolling an additional 29 patients in the expansion phase of the trial. “When these patients were evaluated, we noted an ORR of 84% and an sCR/CR rate of 32%. Prior to this change, the ORR was 68%,” she said. The incidence of AEs, including all grades and ≥ grade 3 CRS and neurotoxicity, were similar between the 2 manufacturing processes.

When looking at the DOR, even after only a median follow up of 7 months, the median DOR was 17 months for the whole cohort. When stratified by dose, the 150 × 10

 dose had an 11.5-month DOR, whereas the median DOR for the 300 × 10

December 5, 2020 - The enriched chimeric antigen receptor T-cell therapy bb21217 improved responses and also prolonged duration of response compared with non-enriched CAR T cells in patients with relapsed/refractory multiple myeloma.


bb21217 Continues to Showcase Durable Responses in Multiple Myeloma

JNJ-4528, a chimeric antigen receptor (CAR) T-cell therapy, continued to demonstrate deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated findings from the phase 1b/2 CARTITUDE-1 (NCT03548207) trial presented during 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Lead author Jesus G. Berdeja, MD, reported that the overall response rate (ORR) was 100%, with a stringent complete response (sCR) rate of 86% (25 out of 29 patients). Further, the progression-free survival (PFS) rate was 86% (95% CI, 67%-95%) at 9 months. Results were 

The objective of the phase 1b portion of CARTITUDE-1 was to determine the safety of the B-cell maturation antigen (BCMA) and confirm the dose for future research. Phase 2 is investigating the efficacy in terms of ORR, defined by the International Myeloma Working Group (IMWG) response criteria.

Patients were eligible to enroll in CARTITUDE-1 if they had progressive multiple myeloma per IMWG criteria, received 3 or more prior therapy regimens for their disease or were double refractory to a proteasome inhibitor and an immunomodulatory drug, and received an anti-CD38 antibody.

After undergoing screening for 28 days followed by apheresis, patients underwent bridging therapy as needed. From day -5 to day -3, patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine. JNJ-4528 was given as a single infusion on day 1, with a target dose of 0.75 × 106 CAR-positive viable T cells/kg.

“A total of 35 patients were enrolled and underwent apheresis, 30 patients were lymphodepleted, and 29 patients were dosed,” said Berdeja, the director of Myeloma Research at the Sarah Cannon Research Institute in Nashville, Tennessee.

The median age of treated patients was 60 years (range, 50-75) and the median number of years since initial diagnosis was 5 (range, 2-16). High-risk cytogenetic profiling revealed 4 patients (15%) with del(17p), 2 (8%) with translocation t(14;16), and 1 (4%) with translocation t(4;14). Patients underwent a median of 5 (range, 3-18) prior lines of therapy, with 76% of patients being penta-exposed, 86% as triple-refractory, 28% considered penta-refractory, and 97% refractory to the last line of therapy.

Phase 1b enrollment (N = 29 treated) is complete and as of the data cut off of January 17, 2020, median follow up was 9 months (range, 3-17 months).

No unusual safety signals were observed in the study, said Berdeja. Cytokine release syndrome (CRS) was common, with 93% of patients demonstrating all-grade severity and 7% of patients with grade 3 or higher toxicity. The median time to onset of CRS was 7 days (range, 2-12) and the median duration was 4 days (range, 2-64). Twenty-three patients (27%) received tocilizumab (Actemra) and 6 (21%) each received anakinra or corticosteroids.

All-grade neurotoxicity consistent with ICANS (immune effector cell–associated neurologic syndrome) was observed in 10% of patients, with 3% of patients having grade 3 or higher toxicity.

“Other toxicities were hematologic, with 100% of patients experiencing grade 3 or 4 neutropenia,” Berdeja said. All-grade thrombocytopenia was observed in 86% patients with 69% (20 of 29) determined to be grade 3 or higher.

Nonhematologic toxicities were infrequent but were led by all-grade diarrhea in 35%, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed in 31% of patients each, and headache in 28%. Grade 3 or higher AST and ALT levels were seen in 7% of patients each.

Regarding cytopenia, Berdeja reported that the median time to first onset of grade 3/4 neutropenia (n = 29) was 0.7 weeks (range, 0.0-1.3) and the median time to recovery was 1.6 weeks (95% CI, 1.3-2.0). For grade 3/4 thrombocytopenia (n = 19), the median time to first onset was 1.9 weeks (range, 0.4-3.5) and the median time to recovery was 5.3 weeks (95% CI, 2.4-8.1).

“Interestingly, we saw that recurrent grade 3/4 cytopenias were observed in some patients but it is unclear if this is a pattern, which we are monitoring closely,” Berdeja said, “Regardless, prolonged severe cytopenias were infrequent.”

All-grade upper respiratory tract infections were reported in 31% of patients. Infections of grade 3/4 severity included pneumonia in 7% of patients, and 3% each for atypical pneumonia, cryptosporidiosis, encephalitis, and sepsis. All infections were reversible, said Berdeja.

Regarding tumor burden reduction, Berdeja said that all but 1 patient had a reduction in their paraprotein.

A very good partial response rate of 97% was reported and Berdeja noted that ORR and depth of response were independent of BCMA expression on myeloma cells at baseline. Median time to response was 1 month (range, 1-3), and median time to CR was 3 months (range, 1-13).

With a median follow-up of 11.5 months (range, 3-17), 22 of 29 patients were alive and progression-free. Berdeja noted 3 deaths in the study that were attributed to CRS, acute myeloid leukemia (treatment unrelated), and disease progression.

Minimal residual disease (MRD) assessment showed that the majority of patients continue to show MRD-negative responses beyond day 28 of treatment. Of the 16 patients with a CR who were evaluable for MRD assessment, 81% were MRD negative at 10-5 or better and 69% were MRD-negative at 10-6.

JNJ-4528 continues to demonstrate a good safety profile, with deep and durable responses. “CRS events were mostly grade 1 to 2 with a median time of onset of 7 days, suggesting that outpatient dosing is feasible,” said Berdeja. He noted that the phase 2 portion of the study is fully enrolled, and phase 2 and 3 studies have been initiated.

Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38:(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505.

The CAR T-cell therapy continued to demonstrate deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma.

JNJ-4528 Continues to Show Durable Responses in Relapsed/Refractory Multiple Myeloma

The chimeric antigen receptor (CAR) T-cell therapy, JNJ-4528, continued to demonstrate deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated findings from the phase 1b/2 CARTITUDE-1 (NCT03548207) trial. Lead author Jesus G. Berdeja, MD, reported that the overall response rate (ORR) was 100%, with a stringent complete response (sCR) rate of 86% (25 out of 29 patients). Further, the progression-free survival (PFS) rate was 86% (95% CI, 67%-95%) at 9 months. Results were presented during 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

After undergoing screening for 28 days followed by apheresis, patients underwent bridging therapy as needed. From day -5 to day -3, patients received 300 mg/m

 of fludarabine. JNJ-4528 was given as a single infusion on day 1, with a target dose of 0.75 × 10

All-grade neurotoxicity consistent with ICANS (immune effector cell—associated neurologic syndrome) was observed in 10% of patients, with 3% of patients having grade 3 or higher toxicity.

Minimal residual disease (MRD) assessment showed that the majority of patients continue to show MRD-negative responses beyond day 28 of treatment. Of the 16 patients with a CR who were evaluable for MRD assessment, 81% were MRD negative at 10

 or better and 69% were MRD-negative at 10

In December 2019, the FDA granted JNJ-4528 a Breakthrough Therapy designation based on initial results of the trial that were presented at the American Society of Hematology Annual Meeting.

Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. 

. 2020;38:(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505

Janssen announces BCMA CAR-T therapy JNJ-4528 granted U.S. FDA breakthrough therapy designation for the treatment of relapsed or refractory multiple myeloma. News release. December 6, 2019. Accessed May 29, 2019. https://www.janssen.com/janssen-announces-bcma-car-t-therapy-jnj-4528-granted-us-fda-breakthrough-therapy-designation

The chimeric antigen receptor T-cell therapy, JNJ-4528, continued to demonstrate deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated findings from the phase 1b/2 CARTITUDE-1 (NCT03548207) trial. 

Updated CARTITUDE-1 Results Continue to Demonstrate Safety, Durable Responses for JNJ-4528 in R/R Multiple Myeloma

A manageable safety profile was observed for the combination of atezolizumab (Tecentriq) and the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (axi-cel; Yescarta), in patients with refractory diffuse large B-cell lymphoma (DLBCL), according to findings from the ZUMA-6 trial (NCT02926833), presented during the 2020 American Association for Cancer Research Virtual Annual Meeting I, April 27 to 28, 2020.

The phase 1/2 study evaluated the safety and efficacy of the combination, and the trial stratified 34 patients into 3 cohorts. After undergoing leukapheresis, all cohorts received a conditioning dose of 30 mg/m

/day of fludarabine plus cyclophosphamide at 500 mg/m

/day for 3 days, followed by an axi-cel infusion of 2 × 10

 CAR T cells/kg. In phase 1, 1200 mg of atezolizumab was administered every 21 days for 4 doses, starting on either day 21, 14, or 1 post axi-cel infusion for cohorts 1, 2, and 3, respectively. After safety review, 28 patients were treated in phase 2 of the study, in which they received the phase 1 atezolizumab/axi-cel dosing schedule of cohort 3.

“The rationale for this study is that after T-cell infusion and upon T-cell activation, CAR T cells will upregulate PD-1,” lead author Caron Jacobson, MD, medical director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, said during the presentation. The investigators administered atezolizumab in concordance with the upregulation of PD-1, which happens after T-cell activation. Checkpoint blockade may enhance the activity of CAR T cells.

The primary end point was incidence of dose-limiting toxicities (DLTs) for phase I and complete response (CR) rate for phase II. Secondary end points included incidence of adverse events (AEs), objective response rate, and CAR T-cell levels in the blood. Jacobson presented pooled data for the patients treated in phase I cohort 3 and phase II (n = 28). Median follow-up was 10.2 months.

Jacobson said results from phase I were presented at the American Society of Hematology Annual Meeting in 2018.

 For this cohort of patients, the median age was 58 years (range, 42-71) and all patients had an ECOG performance status of 0 or 1. The majority of patients had advanced-stage disease, 46% of patients had an International Prognostic Index score of 3 or 4, and 50% of patients had received 3 or more lines of prior therapy.

“All 34 patients enrolled in the phase I and II portions of the study received axi-cel and at least 1 dose of atezolizumab and 24 of 34 patients [74%] received all 4 doses of atezolizumab,” Jacobson said.

Baseline tumor biopsies were evaluated for PD-L1 expression using the Ventana PD-L1 assay. The median baseline tumor cell PD-L1 H score was 40 (range, 0-240). According to the immune infiltrate intensity score, 25% of patients had weak staining, 25% had moderate staining, and 39% had strong staining.

The most common grade 3 or greater treatment-emergent adverse events (TRAEs) occurring in 10% or more of patients was neutropenia (61%), anemia (54%), thrombocytopenia (36%) encephalopathy (25%), and hypophosphatemia (21%). Jacobson said that 39% of grade 3 or greater AEs were attributed to axi-cel, 14% were attributed to atezolizumab, and 25% were attributed to both.

One patient in phase I cohort 3 experienced a DLT of grade 4 thrombocytopenia and neutropenia that lasted longer than 30 days. There was 1 case of grade 5 AE of multiple organ dysfunction unrelated to axi-cel or atezolizumab reported in phase II. The patient developed cytomegalovirus pneumonia and viremia on day 22 following axi-cel infusion that subsequently progressed despite treatment with ganciclovir and was ultimately fatal.

Ninety-six percent of patients reported cytokine release syndrome (CRS) of any grade and 4% of patients experienced grade 3 CRS. There were no grade 4 or 5 CRS events observed. Median onset of CRS was 2 days and median duration was 7 days.

Sixty-eight percent of patients experienced any-grade neurologic events, with 29% experiencing grade 3 or greater severity. The most common neurologic events of any grade were encephalopathy (36%) and aphasia (14%). Median time to onset was 6 days (range, 1-23) and the median duration was 9 days (range, 2-60). Two neurologic events were ongoing at the time of data cut off: 1 case of grade 1 tremor and 1 case of grade 2 hypoesthesia.

Responses were seen in 75% of patients, and at the time of data cut off, 46% had ongoing response. “The median duration of response, progression-free survival, and overall survival have not been reached,” Jacobson said.

When considering all phase I and II portions of the study, 4 patients experienced late conversion, with 3 partial responses converting to complete responses and 1 stable disease converting to complete response.

Product characteristics were generally similar in ZUMA-6 compared with an earlier study, ZUMA-1.

 Jacobson reported that on a whole the, the CD4 to CD8 ratio for ZUMA-6 was similar with ZUMA-1 and there were no meaningful associations between product characteristics in clinical responses.

The kinetics of CAR T-cell expansion were also similar between ZUMA-6 and ZUMA-1 despite the addition of atezolizumab. The investigators reported that median area under the curve was also similar between the 2 studies.

Jacobson said that PD-L1 blockade with atezolizumab after axi-cel infusion has a manageable safety profile similar to that observed in the previous ZUMA-1 trial, with no significant incidence of AEs. Further, efficacy outcomes of axi-cel in combination with atezolizumab appeared to be comparable with those observed in patients treated with axi-cel alone.

“Additional studies involving axi-cel in combination with atezolizumab may be needed to establish an interaction between timing of checkpoint blockade and CAR T-cell treatment,” Jacobson concluded.

Jacobson CA, Westin JR, Miklos DB, et al. Phase 1/2 primary analysis of ZUMA-6: Axicabtagene ciloleucel (Axi-Cel) in combination With atezolizumab (Atezo) for the treatment of patients (Pts) with refractory diffuse large B cell lymphoma (DLBCL). Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I: Virtual; April 27-28, 2020. Abstract CT055. bit.ly/3eZDfb4           

Jacobson CA, Locke FL, Miklos DB, et al. End of phase 1 results from zuma-6: axicabtagene ciloleucel (Axi-Cel) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma. 

. 2018;132(suppl 1; abstr 626). doi: 10.1182/blood-2018-99-111523

Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.

. 2017;377(26):2531-2544. doi: 10.1056/NEJMoa170744

A manageable safety profile was observed for the combination of atezolizumab and the anti-CD19 chimeric antigen receptor T-cell therapy, axicabtagene ciloleucel, in patients with refractory diffuse large B-cell lymphoma.

Positive Safety Profile Reported for Atezolizumab/Axi-Cel Combo in DLBCL

Patients with renal cancer who underwent cytoreductive nephrectomy (CN) and targeted therapy (TT) had improved survival compared with patients who did not undergo the surgery, according to research from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

 Historically, only 3 in 10 such patients undergo the procedure.

The researchers reported that patients who underwent the procedure survived for a median period of 17.1 months compared with 7.7 months for those who didn’t receive the surgery. The finding corroborates the survival benefit of CN with TT in previously reported studies. The 1-, 2-, and 3-year overall survival (OS) rates were 62.7% (95% CI, 61.3%-64.1%), 39.1% (95% CI, 37.7%-40.6%), and 27.7% (95% CI, 26.3%- 29.1%) versus 34.7% (95% CI, 33.7%-35.8%), 17.1% (95% CI, 16.2%-17.9%), and 9.8% (95% CI, 9.1%-10.5%) for CN and non- CN patients, respectively.

“As we’ve learned about the molecular pathways that drive the disease, drugs that specifically target those pathways have come into wide use,” said the co-lead author, Toni Choueiri, MD, in a statement. “It hasn’t been clear whether this has led to a reduction in CN, whether the procedure improves survival in patients being treated with targeted therapy, and whether some categories of patients are more likely than others to receive the surgery,” continued Choueiri, clinical director of the Lank Center for Genitourinary Oncology and director of the Kidney Cancer Center at Dana-Farber Cancer Institute.

Most current guidelines call for CN to be performed in conjunction with TT for patients deemed to be good candidates for the procedure. Studies have shown that patients with poor survival outcomes or with rapidly advancing cancer are less likely to benefit from the surgery. In his study, Choueiri and his associates identified 15,390 patients with metastatic renal cell carcinoma (RCC) who had been treated with TTs between 2006 and 2013. Only 5374 of those patients, or about 35% of the total, underwent CN, the researchers found. The study is the largest sample size to date showing that CN has an OS benefit in patients treated with TT, while adjusting for other factors, according to the researchers. The investigators also found that patients who were younger, privately insured, treated at an academic medical center, and had smaller tumors were more likely to have the surgery performed.

 showed that CN patients had improved OS compared with non-CN patients treated with vascular endothelial growth factor (VEGF) therapy (19.8 vs 9.4 months; HR, 0.44; 

 showed that the median OS of patients with metastatic RCC treated with TT with CN versus without CN was 20.6 months vs 9.5 months, respectively (

The reason why surgery provides a survival benefit for many patients is unclear, said the researchers, but they theorize that the primary tumor may be especially aggressive and drive metastatic growth elsewhere in the body. Removing it may therefore slow the spread of the disease.

Limitations of the study include its retrospective analyses and the National Cancer Database (NCDB) used for the study. The NCDB does not contain information on important preoperative laboratory variables that have been shown to be independent prognostic factors and does not list the exact TT used (eg, VEGF or mammalian target of rapamycin inhibitors), said the researchers. Future investigations will focus on identifying which patients are most likely to benefit from the surgery.

“The study underscores the importance of careful selection of patients who are good candidates for this surgery,” said Maxine Sun, PhD, the co-lead author of the study. “As we become better able to identify patients likely to derive the greatest benefit from surgery, survival rates may further improve.”

Hanna N, Sun M, Meyer CP, et al. Survival analyses of metastatic renal cancer patients treated with targeted therapy with or without cytoreductive nephrectomy: a national cancer data base study [ePub ahead of print]. 

Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic and renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. 

Heng DYC, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. 

Patients with renal cancer who underwent cytoreductive nephrectomy and targeted therapy had improved survival compared with patients who did not undergo the surgery.

Survival Improved With Surgery/Targeted Therapy Combo in Renal Cell Carcinoma

Although clinicians have made significant progress in understanding non—small cell lung cancer (NSCLC) biology and the role of targeted therapies, further clinical research must be performed to identify new molecular subsets of patients who are likely to benefit from personalized care.

An ongoing phase II, four-cohort trial involving capmatinib (INC280), an oral MET inhibitor, will determine the clinical activity of the agent in pretreated patients with advanced NSCLC who have undergone one or two lines of therapy. Patients will be stratified according to 

“There are multiple MET inhibitors that are undergoing investigation and are currently available,” said Rebecca Suk Heist, MD, MPH, an assistant professor at Harvard Medical School and medical oncologist at Massachusetts General Hospital who is participating in the trial as a site investigator. “But we still don’t fully understand these agents’ activities in large populations and in various cohorts.”

 proto-oncogene, whose primary ligand is hepatocyte growth factor (HGF), has been the subject of ongoing clinical research, said Heist. It has been observed that prolonged or continuous activity of the receptor leads to excessive cell proliferation and is related to the development or progression of neoplastic disease. There have been extensive preclinical and clinical studies carried out to elucidate the mechanism of the MET/HGF inhibitory pathway in lung cancer and other solid malignancies. However, questions still remain regarding how to best target this pathway in NSCLC.

Determining which subset of patients with NSCLC would benefit from MET inhibition therapy using a single agent or in combination is the goal of ongoing research. Abnormal 

 activation in cancer correlates with poor prognosis, and aberrantly active 

 triggers tumor growth, formation of new blood vessels that supply the tumor with nutrients, and metastasis through several cell-signaling pathways.

 mutations leading to exon 14 skipping are also an actionable target in NSCLC. Paik et al demonstrated that genomic alterations that promote this aberration lead to oncogenic 

 activation, thus highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.

Capmatinib has demonstrated strong evidence of antitumor activity in an ongoing phase I trial (NCT01324479) in patients with 

-mutated advanced cancers. Early results from the doseescalation study indicated that 3 of 6 patients with 

 wild-type NSCLC participating in the study experienced a partial response with single-agent capmatinib.

The drug was well tolerated across the entire study population (N = 33). The most common all-grade adverse events (AEs) suspected of being related to capmatinib were decreased appetite, nausea, vomiting, and fatigue. AEs of grade 3-4 severity were rare.

In the phase II trial (NCT02414139), patients are prescreened for 

 amplification and mutation status, after which they are assigned to one of four cohorts depending on the gene copy number (GCN): 

 exon 14 skipping mutation regardless of GCN status. The prescreening can occur while patients are receiving other therapy, said Heist. “The exon 14 skipping arm was added because it has grown as a targetable alteration in lung cancer and may be responsive to MET inhibitors,” said Heist.

Eligible patients must be aged ≥18 years with stage IIIB/IV NSCLC that is 

 wild-type. They also must have Eastern Cooperative Oncology Group performance status scores of 0—1. Capmatinib will be administered twice daily on a continuous dosing schedule 12 hours apart. Each cohort will contain about 69 patients, for a total enrollment of about 276 patients.

The primary endpoints are the overall response rate and the proportion of patients with a complete or partial response as assessed by blinded independent review. Secondary endpoints include duration of response, progression- free survival, and overall survival.

 is a targetable alteration in lung cancer,” Heist said. “As we have seen with other targets, we can change the natural history of a person’s disease if we are able to hit that target effectively. The hope from this study is that there will emerge a defined cohort in which people will derive a significant benefit.”

Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. 

Bang YJ, Su WC, Nam DH, et al. Phase I study of the safety and efficacy of INC280 in patients with advanced MET-dependent solid tumors. 

An ongoing phase II, four-cohort trial involving
capmatinib (INC280), an oral MET inhibitor,
will determine the clinical activity of the agent
in pretreated patients with advanced non-small cell lung cancer
who have undergone one or two lines of therapy.